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Nat Med. 2015 Jun;21(6):619-27. doi: 10.1038/nm.3862. Epub 2015 May 18.

The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes.

Author information

1
1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
2
Cell Isolation and Transplantation Center, Department of Surgery, University Hospitals and University of Geneva, Geneva, Switzerland.
3
Université de Lille 2, INSERM, European Genomic Institute for Diabetes, Lille Cedex, France.
4
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.

Abstract

Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.

PMID:
25985365
DOI:
10.1038/nm.3862
[Indexed for MEDLINE]

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